Breast cancer is the most common malignancy in women and approximately one in ten women in the US will develop breast cancer during her lifetime. The long-term objective of this proposal is to study how the breast cancer tumor suppressor protein, BRCA1, contributes to the prevention of familial breast and ovarian cancers. A key lacuna in our current knowledge is to understand why BRCA1 may be specific for breast and ovary tissues, since mutations in BRCA1 do not result in an increased risk for other cancers. This project will examine whether BRCA1 may be specific for breast and ovary tissues because of its role in transcriptional regulation of estrogen receptor (ER) responsive promoters. Estrogens play a pivotal role in the initiation and progression of breast tumors. We have identified a protein, COBRA1, which interacts with BRCA1 and also with ER. This project tests the hypothesis that a complex of BRCA1/COBRA1 may be recruited to ER responsive promoters to repress transcription. One aim of this proposal is to determine the functional link between COBRA1, BRCA1 and ER in transcriptional regulation. In addition, these studies will examine if COBRA1 contributes to the development of breast cancer. Understanding how COBRA1 expression influences breast cancer may provide new avenues for molecular diagnosis and treatment of breast cancers.